John F. Kerrigan, MD, Co-Director, Hypothalamic Hamartoma Program Barrow Neurological Institute
What Have We Learned About Treating HH and Epilepsy? Part I
While there are many interesting issues to discuss about hypothalamic hamartoma (HH), and there are recent research discoveries in a number of areas, I also realize that most visitors to this website are here because a family member has HH, and getting some answers about treatment right now is the highest priority. I will devote this column and the one that follows to what we have learned over the past decade about treating patients with HH.
Recall that there are two different clinical conditions associated with HH (the collection of symptoms and clinical signs that are common to a group of patients is referred to as a syndrome). The first syndrome consists of HH patients with early signs of puberty (central precocious puberty). These children usually do not have a lot of neurological or developmental problems. They can be treated medically with administration of a compound (Lupron, also known as leuprolide acetate) given by intramuscular injection once per month, which halts the further development of puberty until the medicine is stopped. For these HH patients, surgery is usually not required, and they are typically managed by an endocrinologist, without the need to be seen by a neurologist or neurosurgeon.
The second syndrome consists of the patients that have epilepsy, usually beginning with gelastic (laughing) seizures, who also usually have other neurological symptoms such as developmental delay (or even loss of developmental skills) and behavioral problems. (Roughly 40% of this group can also have central precocious puberty.) This is the group of patients that we will discuss further here.
What kinds of research studies are available?
The ideal circumstance for proving that one treatment method is better than another is the controlled study (or controlled clinical trial) in which a group of patients is randomly assigned to receive one treatment, and a second group is assigned to another treatment (or perhaps no treatment at all). In this way, researchers can make a direct comparison between the two different groups and their treatment results (also called treatment outcome).
It is important to realize that there are no controlled studies of treatment methods for patients with HH. The lack of controlled studies is unfortunate, but understandable. They are very expensive to perform, and it is a challenge to recruit patients (or their parents) to participate in a study in which a coin toss will decide whether one gets surgery or not, or perhaps different kinds of surgery.
Several very important research studies on HH treatment have been published over the past 10 years, but all have been uncontrolled studies (that is, all patients in the study cohort received the same treatment). While this is preferable to a complete absence of published reports, or reports describing the experience with one or two patients, it has to be recognized that the medical literature cannot claim to have proven that one approach is superior to another in a completely unbiased manner.
Principles of Management
Based upon everything we have learned at this point, the treatment for epilepsy associated with HH should be based upon the following principles:
1. Anti-epilepsy drugs (AEDs) are usually unsuccessful in completely controlling seizures resulting from HH. That is, patients with HH are usually “treatment-resistant”.
2. Gelastic seizures arise from the HH lesion. That is, the HH is “intrinsically epileptogenic”.
3. Because of this, interventions directed at removing, injuring, or completely disconnecting the HH can be successful for controlling seizures.
4. Epilepsy associated with HH can be a progressive condition for many patients, with the development of other seizure types, and with deterioration in cognition and behavior.
5. Because of this, earlier treatment may be preferable, particularly for patients who are getting worse with respect to their seizures, cognitive function, or behavior.
6. The best treatment choice is individualized to the circumstances of each patient. The most important considerations include 1) whether the patient has stable or progressive symptoms (which influences the urgency of treatment), and 2) the exact anatomy of the HH lesion, particularly with respect to how the HH lesion attaches to the normal brain (which influences the surgical decision about the best approach to the HH).
HH Classification and Surgical Anatomy
We will explore the different treatment options and the published evidence for or against each one in Part II of this Research Corner column. However, a necessary step before that discussion is to understand the anatomy of HH lesions, since this has a huge influence on the decision-making process for selecting the best therapy.
Several authors have proposed classification schemes for HH lesions, including Valdueza (Valdueza et al, 1994), Delalande and Fohlen (Delalande & Fohlen, 2003), and Regis (Regis et al, 2004). My preference is to use the Delalande and Fohlen classification, as the subtypes relate to the surgical anatomy in a rather simple and direct fashion. [“Surgical anatomy’ refers to the anatomy as it is understood and utilized by the neurosurgeon, that is, the safest and most effective way to get from here to there inside the skull. The shortest distance may not be the best.]
The figure shows a representation of the Delalande and Fohlen classification.
Type I: These are HH lesions that attach below the floor of the third ventricle, with a horizontal plane of attachment to the underside of the hypothalamus. If these lesions have a narrow base of attachment in the anterior (most forward) region of the hypothalamus, they may be associated only with central precocious puberty, but a broader base of attachment, especially if it includes the more posterior portion of the hypothalamus, may have epilepsy and other neurological problems. Because of the site of attachment, these HH lesions are best approached surgically from below (that is, coming from below the temporal or frontal lobes).
Type II: These are HH lesions that attach completely within the third ventricle (above the floor of the third ventricle), with a vertical plane of attachment. These HH lesions (and the ones that follow) are highly associated with epilepsy. Because of the vertical plane of attachment, and their often small size, this type is often ideal for endoscopic resection (or, if the patients is stable, gamma knife radiosurgery).
Type III: These are HH lesions that attach both above and below the floor of the third ventricle (and, accordingly, have both vertical and horizontal planes of attachment). These lesions may be approached from above (either the open transcallosal approach or the endoscopic approach) or from below, or with a combination of the two. If the patient is stable, these type III lesions may also be treated with gamma knife radiosurgery.
Type IV: These are defined as “giant” HH lesions by Delalande and Fohlen, although quantitative criteria for the exact meaning of “giant” were not suggested. Our group has used a volume of 8 or 10 cm3, depending upon the paper. These lesions are likely to be attached bilaterally to the hypothalamus, with planes of attachment both above and below the floor of the third ventricle.
In Part II of this column, we will examine the published evidence relating to the various surgical approaches that have now been identified for treating HH, and the lesions types and patient features that appear to be most suited to each of treatment approach.
Delalande O, Fohlen M. Disconnecting surgical treatment of hypothalamic hamartoma in children and adults with refractory epilepsy and proposal of a new classification. Neurol Med Chir (Tokyo) 2003;43:61-68.
Regis J, Hayashi M, Eupierre LP, Villeneuve N, Bartolomei F, Brue T, Chauvel P. Gamma knife surgery for epilepsy related to hypothalamic hamartoma. Acta Neurochir Suppl 2004;91:33-50.
Valdueza JM, Cristante L, Dammann O, Bentele K, Vortmeyer A, Saeger W, Padberg B, Freitag J, Herrmann H-D. Hypothalamic hamartomas: with special reference to gelastic epilepsy and surgery. Neurosurgery 1994;34:949-958.